Centre for Cancer Research - Theses
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ItemImmune markers to predict response to neoadjuvant chemoradiotherapy and identifying methods to incorporate immunotherapy in locally advanced rectal cancer( 2018)The standard of care for locally advanced rectal cancer (T3-4 +/- N+) is neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME). However, this has been challenged recently with increasing interest and trials assessing the efficacy and safety of avoiding TME. This concept is known as the “watch and wait” strategy, if patients were deemed to have clinical complete response (cCR). The current limitation is the risk of local tumour regrowth rate between 20-30%, as cCR is not equivalent to pathological complete response (pCR). Therefore, this thesis describes the development of a novel immune cytotoxic assay for measuring patient-matched cytotoxic T cell-mediated killing of rectal cancer organoids. Subsequently a proof of principle prospective observational study was conducted, showing in those patients with pCR, their cytotoxic T cell-mediated killing were highest when compared to non-pCR. Furthermore, this was a stark difference without overlapping of 95% confidence interval when compared to the partial and non-responding T cell-mediated killing of rectal cancer organoids. At the other end of the spectrum, those that had failed to achieve any response to neoadjuvant therapy will not have any other therapeutic option left to increase their tumour response rate. Promising emerging therapies employing immunotherapy by check-point inhibition and/or targeted-vaccine are now highly relevant, especially inhighly immunogenic colorectal cancer such as microsatellite instability high subset due to high somatic mutation. A similar tumour microenvironment has been documented after induction radiotherapy, with success of check-point inhibition shown only in mouse models. Using the immune cytotoxic assay, this thesis demonstrates the increased in patient-matched T cell-mediated killing of rectal cancer organoids in the presence of check-point inhibition. This opens another avenue to explore the utility of immunotherapy using a T cell-organoid model, with the potential for investigating and identifying novel markers to immune resistance.